Controlled release formulation (albuterol)

ABSTRACT

A sustained release pharmaceutical formulation and methods of making and using the same are provided. The sustained release pharmaceutical formulation includes a sustained release excipient including a gelling agent, an inert pharmaceutical diluent, an optional hydrophobic material and/or hydrophobic coating, and a medicament for sustained oral administration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 08/553,008, filedNov. 3, 1995, now U.S. Pat. No. 5,662,933, which is acontinuation-in-part of Ser. No. 08/118,924, filed Sep. 9, 1993, nowU.S. Pat. No. 5,455,046.

FIELD OF THE INVENTION

The present invention relates to controlled release formulations whichmay be blended with a wide range of therapeutically active medicamentsand made into controlled release solid dosage forms for oraladministration.

BACKGROUND OF THE INVENTION

The advantages of controlled release products are well known in thepharmaceutical field and include the ability to maintain a desired bloodlevel of a medicament over a comparatively longer period of time whileincreasing patient compliance by reducing the number administrations.These advantages have been attained by a wide variety of methods. Forexample, different hydrogels have been described for use in controlledrelease medicines, some of which are synthetic, but most of which aresemi-synthetic or of natural origin. A few contain both synthetic andnon-synthetic material. However, some of the systems require specialprocess and production equipment, and in addition some of these systemsare susceptible to variable drug release.

Oral controlled release delivery systems should ideally be adaptable sothat release rates and profiles can be matched to physiological andchronotherapeutic requirements. In U.S. Pat. Nos. 4,994,276, 5,128,143,and 5,135,757, hereby incorporated by reference in their entireties, itis reported that a controlled release excipient which is comprised of asynergistic combination of heterodisperse polysaccharides (e.g., aheteropolysaccharide such as xanthan gum in combination with apolysaccharide gum capable of cross-linking with theheteropolysaccharide, such as locust bean gum, in an aqueousenvironment) is capable of being processed into oral solid dosage formsusing either direct compression (i.e., dry granulation), followingaddition of drug and lubricant powder, conventional wet granulation, ora combination of the two. The release of the medicament from theformulations therein proceeded according to zero-order or first-ordermechanisms.

The controlled release excipients disclosed in U.S. Pat. Nos. 4,994,276,5,128,143, and 5,135,757 are commercially available under the trade nameTIMERx® from Edward Mendell Co., Inc., Patterson, N.Y., which is theassignee of the present invention.

European Pat. No. 234670 B describes a controlled-release pharmaceuticalformulation containing xanthan gum wherein the xanthan gum comprisesfrom about 7.5 to about 28 percent, by weight, of the formulation exceptfor a formulation wherein the controlled release carrier comprises amixture of 15-50 parts by weight dimethylsiloxane, 30-100 parts byweight silicic acid, 30-100 parts by weight mannans or galactans or amixture thereof, 50-150 parts by weight xanthans and 5-75 parts byweight micronized seaweed.

However, heretofore there has been no teaching of a controlled releaseformulation providing a novel and unexpected combination of suitableproportions of a homopolysaccharide such as, e.g., xanthan gum, aheteropolysaccharide, such as, e.g., locust bean gum, together with aninert diluent and a pharmacologically acceptable hydrophobic material,so as to provide an improvement in controlled release properties forsuch an active medicament.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide acontrolled release formulation for a therapeutically active medicament.

It is a further object of the present invention to provide a method forpreparing a controlled release formulation for a therapeutically activemedicament.

It is yet another object of the present invention to provide acontrolled release excipient which may be used in the preparation of asustained release oral solid dosage form of a therapeutically activemedicament that provides an even rate of release of an activemedicament.

It is a further object of the present invention to provide a controlledrelease excipient which, when combined with an effective amount of abronchodilator, such as albuterol, is suitable for providing a sustainedrelease of that medicament so as to provide a therapeutically effectiveblood level of the medicament for e.g., 12 or 24 hours, without allowingan excessive early release of medication, and where the release kineticsare unaffected by the contents of the patient's gastrointestinal tract.

It is yet a further object of the present invention to provide a methodfor treating patients with an active medication in controlled releaseform.

The above-mentioned objects and others are achieved by virtue of thepresent invention, which relates in-part to a controlled releaseformulation comprising a therapeutically effective amount of amedicament, and a controlled release excipient comprising a gellingagent and a swelling agent, such as, for example, a homopolysaccharide,a heteropolysaccharide, an inert diluent.

In certain preferred embodiments of the invention, the ratio of theheteropolysaccharide gum to the homopolysaccharide gum is from about 1:3to about 3:1. More preferably, the ratio is about 1:1. Preferably, theheteropolysaccharide gum includes xanthan gum and the homopolysaccharidegum includes locust bean gum.

The present invention is also related to a sustained release oral soliddosage form for albuterol or salts or derivatives thereof in an amountnecessary to render a therapeutic effect in a human patient. Thealbuterol is present in an amount ranging from, e.g., about 2 throughabout 50% by weight of the total formulation, or preferably from about 1through about 10% by weight or more preferably from about 1 throughabout 6% by weight of the total formulation.

The dosage form includes an inert pharmaceutical diluent so that theratio of the inert diluent to the gelling agent is from about 1:8 toabout 8:1. Preferably, the diluent is from the group consisting of apharmaceutically acceptable saccharide, polyhydric alcohol, apre-manufactured direct compression diluent, and mixtures of any of theforegoing. The diluent can also be a saccharide such as sucrose,dextrose, lactose, microcrystalline cellulose, fructose, xylitol,sorbitol, a starch, and mixtures thereof.

The dosage form optionally includes a pharmaceutically acceptablehydrophobic material. Any pharmaceutically acceptable hydrophobicmaterial may be suitably employed. Suitable hydrophobic materialsinclude carboxymethylcellulose, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl-methylcellulose phthalate,ethylcellulose, a copolymer of acrylic and methacrylic and esters,waxes, shellac, zein, hydrogenated vegetable oils, and mixtures of anyof the foregoing. Preferably, the hydrophobic material selected fromcellulose ether, a cellulose ester and an alkylcellulose, such asethylcellulose and carboxymethylcellulose. The hydrophobic material maybe included in the dosage form in an amount effective to slow thehydration of the gelling agent when exposed to an environmental fluid.

The hydrophobic material is preferably present in an amount ranging fromabout 1 through about 90%, by weight, of the solid dosage form, and canalso be present in an amount ranging from about 25% through about 50%,by weight, of the solid dosage form.

The medicament can be any medicament for which an orally administeredcontrolled release form is desired. Preferably, the formulation isprepared to include a pharmaceutically effective amount of albuterol ora salt or derivative thereof.

The controlled release solid dosage form can be prepared in anyconventional orally administered dosage form, including a tablet, as agranular form and as a granular form administered in a gelatin capsulecontaining a sufficient amount of the granules to provide an effectivedose of the included therapeutically active medicament. For a tabletdosage form, at least part of a surface of the tablet can optionally becoated with a hydrophobic material to a weight gain from about 1 toabout 20 percent, by weight. Further, a granular dosage form canoptionally be coated with a hydrophobic coating material to a weightgain that ranges from about 1% to about 20%. The hydrophobic materialcan be selected from, e.g., a cellulose ether, a cellulose ester and analkylcellulose. The hydrophobic material can optionally be appliedbefore, during or after the process of tableting. In addition, if thereis a need for an early release of the active medicament, the coating canoptionally be formulated to include from about 10 to about 40 percent ofthe total amount of the active medicament in a quick release externallayer.

The invention also relates to methods for preparing a controlled releasesolid dosage form as described above for providing an active medicamentin an amount effective for treating a patient for from 12 to about 24hours. The method includes the steps of preparing a sustained releaseexcipient comprising from about 10 to about 99 percent by weight of agelling agent comprising a heteropolysaccharide gum and ahomopolysaccharide gum capable of cross-linking saidheteropolysaccharide gum when exposed to an environmental fluid, theratio of said heteropolysaccharide gum to said homopolysaccharide gumbeing from about 1:3 to about 3:1, and from about 0 to about 89 percentby weight of an inert pharmaceutical diluent, and optionally from about1 to 90% by weight of a pharmaceutically acceptable hydrophobicmaterial; and adding an effective amount of a medicament to provide afinal product having a ratio of medicament to gelling agent from about1:3 to about 1:8, so that a gel matrix is created.

The medicament to be added is preferably albuterol or salts orderivatives thereof in an amount ranging from, e.g., about 2 to about50% by weight of the total formulation, or preferably from about 1 toabout 10% by weight or more preferably from about 1 to about 6% byweight of the total formulation.

The resulting mixture of the sustained release excipient preferablyincludes from about 10 to about 75 percent gelling agent, from about 0to about 90% hydrophobic material and from about 30 to about 75 percentinert diluent. Thereafter, the dosage form can be tableted, granulatedwith a pharmaceutically acceptable hydrophobic material or placed ingelatine capsules. Optionally the tablet can be coated with ahydrophobic coating to a weight gain from about 1% to about 20%.

Preferably, the medicament is albuterol or a salt or derivative thereofin an amount effective to provide therapeutically effective blood levelsof said medicament for at least 24 hours.

The present invention is further related to a method of treating apatient comprising orally administering the sustained release albuteroltablets to a patient, thereby providing therapeutically effective bloodlevels of the medicament for at least about 24 hours.

By "sustained release" it is meant for purposes of the present inventionthat the therapeutically active medicament is released from theformulation at a controlled rate such that therapeutically beneficialblood levels (but below toxic levels) of the medicament are maintainedover an extended period of time, e.g., providing a 24 hour dosage form.

The term "environmental fluid" is meant for purposes of the presentinvention to encompass, e.g., an aqueous solution, such as that used forin-vitro dissolution testing, or gastrointestinal fluid.

In one aspect the invention provides formulations having particularpharmacokinetic properties. Thus, simply by way of example, theinvention provides formulations suitable for oral administration that,when orally administered to a patient, provide a medicament plasmaconcentration-time curve with an area under the curve-calculated toinfinity ("AUC.sub.∞ "), ranging from about 89 to about 150(ng-hours/ml) or even from about 112 to about 129 (ng-hours/ml).Further, the formulations according to the invention can provide, e.g.,an AUC.sub.∞ ranging from about 57 to about 157 (ng-hours/ml) (fastingpatient) or from about 75 to about 162 (ng-hours/ml) (fed patient).

In addition, for example, mean peak plasma concentrations (Cmax) rangingfrom about 7 to about 12 ng/ml or even from about, 9.5 to about 12ng/ml. are provided. Further, the formulations according to theinvention can provide, e.g., a Cmax ranging from about 4.5 to about 19ng/ml (fasting patient) or from about 6 to about 16 ng/ml (fed patient).

In another example, time to mean peak plasma concentration (Tmax)ranging from about 3 to about 10 hours or even from about 3.5 to about 8hours are provided. Further, the formulations according to the inventioncan provide, e.g., a Tmax ranging from about 3 to about 6 hours (fastingpatient) or from about 3 to about 8 hours (fed patient).

In a further example, the formulation according to the inventionprovides, for example, ratios of AUC.sub.∞ (fasting patient) toAUC.sub.∞ (fed patient) that range from about 0.50 to about 0.70.

Further still, the formulation provides, for example ranges of Cmax(fasting patient) divided by Cmax (fed patient) from about 0.90 to about1.10.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a dissolution profile of an albuterol containing tabletformulated according to Table 14 and Table 15 (Example 10) and conductedas a Type II dissolution with a pH change to simulate gastric passageand stirring at 50 rpm.

FIG. 2 shows a dissolution profile of an albuterol containing tabletformulated according to Table 14 and Table 15 (Example 10) and conductedas a Type III dissolution with a pH change to simulate gastric passageand stirring at 15 rpm.

FIG. 3 shows an albuterol plasma profile of provided by ingestion of analbuterol containing tablet formulated according to Table 14 and Table15 (Example 10): solid circles mark curve of plasma profile in fedsubject; open circles mark curve of plasma profile in fasted subject.

DETAILED DESCRIPTION

As reported in U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757, thedisclosures of which are hereby incorporated by reference herein intheir entireties, the heterodisperse excipient comprises a gelling agentof both hetero- and homo-polysaccharides which exhibit synergism, e.g.,the combination of two or more polysaccharide gums produce a higherviscosity and faster hydration than that which would be expected byeither of the gums alone, the resultant gel being faster-forming andmore rigid.

In the present invention, it has been found that a sustained releaseexcipient comprising only the gelling agent (heterodispersepolysaccharides, e.g., xanthan gum and locust bean gum, may not besufficient to provide a suitable sustained release of an activemedicament to provide a 12 or 24 hour formulation, when the formulationis exposed to a fluid in an environment of use, e.g. an aqueous solutionor gastrointestinal fluid.

In certain embodiments, the present invention is related to thesurprising discovery that by granulating the sustained release excipientwith a solution or dispersion of a pharmacologically acceptablehydrophobic material prior to admixture of the sustained releaseexcipient with the medicament and tableting, the medicament may providetherapeutically effective blood levels for extended periods of time,e.g., from about 12 to about 24 hours. The hydrophobic material ispresent in a range from about 0 to about 90%, by weight, of thesustained release excipient and in a preferred embodiment, is present ina range from about 1 to 20 percent of the sustained release excipient orfrom about 25 to about 75 percent of the sustained release excipient.

The sustained release excipient can be granulated with apharmacologically acceptable hydrophobic material such as, for, example,an alkylcellulose, a cellulose ether, a cellulose ester. In particular,the hydrophobic material can be alkylcellulose such ascarboxymethylcellulose ("CMC"), cellulose acetate phthalate ("CAP"),hydroxypropylmethylcellulose phthalate ("HPMCP") or a polyvinyl acetatepolymer such as polyvinyl acetate phthalate ("PVAP").

In certain preferred embodiments of the present invention, the sustainedrelease excipient is prepared by mixing the gelling agent and an inertdiluent. The gelling agent preferably ranges, e.g., from about 10 toabout 75 percent of the sustained release excipient. Thereafter, themixture is granulated with a solution or dispersion of a hydrophobicmaterial in an amount effective to slow the hydration of the gellingagent without disrupting the hydrophilic matrix. Next, the medicament isadded, and the resultant mixture is tableted.

In other preferred embodiments of the present invention, the tabletsprepared as set forth above are then coated with a hydrophobic materialto a weight gain from about 1 to about 20 percent by weight. Thehydrophobic material can be an alkylcellulose such as, for example, anaqueous dispersion of ethylcellulose (commercially available, forexample, as Aquacoat®, available from FMC or Surelease®, available fromColorcon).

The term "heteropolysaccharide" as used in the present invention isdefined as a water-soluble polysaccharide containing two or more kindsof sugar units, the heteropolysaccharide having a branched or helicalconfiguration, and having excellent water-wicking properties and immensethickening properties.

An especially preferred heteropolysaccharide is xanthan gum, which is ahigh molecular weight (>10⁶) heteropolysaccharide. Other preferredheteropolysaccharides include derivatives of xanthan gum, such asdeacylated xanthan gum, the carboxymethyl ether, and the propyleneglycol ester.

The homopolysaccharide gums used in the present invention which arecapable of cross-linking with the heteropolysaccharide include thegalactomannans, i.e., polysaccharides which are composed solely ofmannose and galactose. Galactomannans which have higher proportions ofunsubstituted mannose regions have been found to achieve moreinteraction with the heteropolysaccharide. Locust bean gum, which has ahigher ratio of mannose to galactose, is especially preferred ascompared to other galactomannans such as guar and hydroxypropyl guar.

The controlled release properties of the formulations of the presentinvention may be optimized when the ratio of heteropolysaccharide gum tohomopolysaccharide material is about 1:1, although heteropolysaccharidegum in an amount of from about 20 to about 80 percent or more by weightof the heterodisperse polysaccharide material provides an acceptableslow release product. The combination of any homopolysaccharide gumsknown to produce a synergistic effect when exposed to aqueous solutionsmay be used in accordance with the present invention. It is alsopossible that the type of synergism which is present with regard to thegum combination of the present invention could also occur between twohomogeneous or two heteropolysaccharides. Other acceptable gellingagents which may be used in the present invention include those gellingagents well-known in the art. Examples include vegetable gums such asalginates, carrageenan, pectin, guar gum, xanthan gum, modified starch,hydroxypropylmethylcellulose, methylcellulose, and other cellulosicmaterials such as sodium carboxymethylcellulose andhydroxypropylcellulose. This list is not meant to be exclusive.

The combination of xanthan gum with locust bean gum with or without theother homopolysaccharide gums is an especially preferred gelling agent.The chemistry of certain of the ingredients comprising the excipients ofthe present invention such as xanthan gum is such that the excipientsare considered to be self-buffering agents which are substantiallyinsensitive to the solubility of the medicament and likewise insensitiveto the pH changes along the length of the gastrointestinal tract.

The inert pharmaceutical diluent (i.e., filler) of the sustained releaseexcipient preferably comprises a pharmaceutically acceptable saccharide,including a monosaccharide, a disaccharide, or a polyhydric alcohol, apre-manufactured direct compression diluent, and/or mixtures of any ofthe foregoing. Examples of suitable inert pharmaceutical fillers includesucrose, dextrose, lactose, microcrystalline cellulose, fructose,xylitol, sorbitol, a starch, mixtures thereof and the like. However, itis preferred that a soluble pharmaceutical filler such as lactose,dextrose, sucrose, or mixtures thereof be used. If the mixture is to bemanufactured without a wet granulation step, and the final product is tobe tableted, it is preferred that all or part of the inert diluentcomprise a pre-manufactured direct compression diluent. Such directcompression diluents are widely used in the pharmaceutical arts, and maybe obtained from a wide variety of commercial sources. Examples of suchpre-manufactured direct compression excipients include Emcocel®(microcrystalline cellulose, N.F.), Emdex® (dextrates, N.F.), andTab-Fine® (a number of direct-compression sugars including sucrose,fructose, and dextrose), all of which are commercially available fromEdward Mendell Co., Inc., Patterson, N.Y.). Other direct compressiondiluents include Anhydrous lactose (Lactose N.F., anhydrous directtableting) from Sheffield Chemical, Union, N.J. 07083; Elcems® G-250(Powdered cellulose, N.F.) from Degussa, D-600 Frankfurt (Main) Germany;Maltrin® (Agglomerated maltodextrin) from Grain Processing Corp.,Muscatine, Iowa 52761; Neosorb 60® (Sorbitol, N.F., direct-compression)from Roquette Corp., 645 5th Ave., New York, N.Y. 10022; Nu-Tab®(Compressible sugar, N.F.) from Ingredient Technology, Inc., Pennsauken,N.J. 08110; Polyplasdone XL® (Crospovidone, N.F., cross-linkedpolyvinylpyrrolidone) from GAF Corp., New York, N.Y. 10020; Primojel®(Sodium starch glycolate, N.F., carboxymethyl starch) from GenerichemCorp., Little Falls, N.J. 07424; Solka Floc® (Cellulose floc) fromEdward Mendell Co., Carmel, N.Y. 10512; Fast-Flo Lactose® (Lactose N.F.,spray dried) from Foremost Whey Products, Baraboo, Wis. 53913 and DMVCorp., Vehgel, Holland; and Sta-Rx 1500® (Starch 1500) (Pregelatinizedstarch, N.F., compressible) from Colorcon, Inc., West Point, Pa. 19486.However, it is preferred that a soluble pharmaceutical filler such aslactose, dextrose, sucrose, or mixtures thereof be used.

In certain embodiments of the present invention, the sustained releaseexcipient comprises from about 10 to about 99 percent by weight of agelling agent comprising a heteropolysaccharide gum and ahomopolysaccharide gum and from about 0 to about 89 percent by weight ofan inert pharmaceutical diluent. In other embodiments, the sustainedrelease excipient comprises from about 10 to about 75 percent gellingagent, and from about 30 to about 75 percent inert diluent. In yet otherembodiments, the sustained release excipient comprises from about 30 toabout 75 percent gelling agent and from about 15 to about 65 percentinert diluent.

The sustained release excipient of the present invention may be furthermodified by incorporation of a hydrophobic material which slows thehydration of the gums without disrupting the hydrophilic matrix. This isaccomplished in preferred embodiments of the present invention bygranulating the sustained release excipient with the solution ordispersion of a hydrophobic material prior to the incorporation of themedicament. The hydrophobic material may be selected from analkylcellulose such as ethylcellulose such as carboxymethyl-cellulose("CMC"), other hydrophobic cellulosic materials, acrylic and/ormethacrylic ester polymers, copolymers of acrylic and methacrylicesters, zein, waxes, other hydrophobic cellulosic materials, celluloseacetate phthalate ("CAP"), hydroxypropylmethylcellulose phthalate("HPMCP") or a polyvinyl acetate polymer such as polyvinyl acetatephthalate ("PVAP"), hydrogenated vegetable oils, and any otherpharmaceutically acceptable hydrophobic material known to those skilledin the art. The amount of hydrophobic material incorporated into thesustained release excipient is that which is effective to slow thehydration of the gums without disrupting the hydrophilic matrix formedupon exposure to an environmental fluid.

In certain preferred embodiments of the present invention, thehydrophobic material is included in the sustained release excipient inan amount from about 1 to about 20 percent by weight. The solvent forthe hydrophobic material may be an aqueous or organic solvent, ormixtures thereof.

Examples of commercially available alkylcelluloses are Aquacoat®(aqueous dispersion of ethylcellulose available from FMC), Surelease®(aqueous dispersion of ethylcellulose available from Colorcon). Examplesof commercially available acrylic polymers suitable for use as thehydrophobic material include Eudragit® RS and RL (copolymers of acrylicand methacrylic acid esters having a low content (e.g, 1:20 or 1:40) ofquaternary ammonium compounds).

Once the sustained release excipient of the present invention has beenprepared, it is then possible to blend the same with the medicament,e.g., in a high shear mixer. In one embodiment, the formulation isprepared by dry blending the components, e.g., a heteropolysaccharide, ahomopolysaccharide, an inert filler, and a hydrophobic material,optionally followed by the addition of a suitable amount of water, withcontinued blending, followed by dry granulation in a fluid bed dryer andthen milling of the resulting granulation product.

A wide variety of therapeutically active agents can be used inconjunction with the present invention. The therapeutically activeagents (e.g., pharmaceutical agents) which may be used in thecompositions of the present invention include drugs ranging insolubility from water soluble to water insoluble. Examples of suchtherapeutically active agents include antihistamines (e.g.,dimenhydrinate, diphenhydramine, chlorpheniramine anddexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine,morphine, dihydromorphone, oxycodone, etc.), non-steroidalanti-inflammatory agents (e.g., naproxyn, diclofenac, indomethacin,ibuprofen, sulindac), anti-emetics (e.g., metoclopramide),anti-epileptics (e.g., phenytoin, meprobamate and nitrazepam),vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine),anti-tussive agents and expectorants (e.g., codeine phosphate),anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g.atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g.,ethacrynic acid, bendrofluazide), anti-hypotensives (e.g., propranolol,clonidine), antihypertensives (e.g., clonidine, methyldopa),bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone,triamcinolone, prednisone), antibiotics (e.g., tetracycline),antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics,sedatives, decongestants, laxatives, vitamins, stimulants (includingappetite suppressants such as phenylpropanolamine). The above list isnot meant to be exclusive.

In a preferred embodiment, the therapeutically active agents aresympathomimetics such as, dobutamine hydrochloride, dopaminehydrochloride, ephedrine sulfate, epinephrine, fenfluraminehydrochloride, isoetharine, isoproterenol, mephentermine sulfate,metaproterenol sulfate, metaraminol bitartrate, methoxaminehydrochloride, norepinephrine bitartrate, phenylephrine hydrochloride,phenylpropanolamine hydrochloride, pseudoephedrine, ritodrinehydrochloride, terbutaline sulfate, tetrahydrozoline hydrochloride,triprolidine and pseudoephedrine, xylometazoline hydrochloride,isoproterenol and dobutamine as well as beta2 selective adrenergicagonists, including, for example, terbutaline, albuterol, isoetharine,pirbuterol and bitolterol (GOODMAN AND GILMAN's, THE PHARMACOLOGICALBASIS OF THERAPEUTICS, Eighth Edition, the disclosure of which isincorporated herein by reference in its entirety).

Generally any flavoring or food additive such as those described inChemicals Used in Food Processing, pub 1274 by the National Academy ofSciences, pages 63-258, incorporated herein in its entirety, may beused. Generally, the final product may include from about 0.1% to about5% by weight flavorant.

The tablets of the present invention may also contain effective amountsof coloring agents, (e.g., titanium dioxide, F.D. & C. and D. & C. dyes;see the Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5, pp.857-884, hereby incorporated by reference in its entirety), stabilizers,binders, odor controlling agents, and preservatives.

Alternatively, the inventive formulation can be utilized in otherapplications wherein it is not compressed. For example, the granulatecan be admixed with an active ingredient and the mixture then filledinto capsules. The granulate can further be molded into shapes otherthan those typically associated with tablets. For example, the granulatetogether with active ingredient can be molded to "fit" into a particulararea in an environment of use (e.g., an implant). All such uses would becontemplated by those skilled in the art and are deemed to beencompassed within the scope of the appended claims.

A hydrophobic material (e.g., a hydrophobic polymer) may be dissolved inan organic solvent or dispersed in an aqueous solution. Thereafter, thehydrophobic material may be used to coat the granulate ofmedicament/sustained release excipient. The granulate may be coated withthe hydrophobic coating to a weight gain of, e.g., from about 1 to about20 percent, and preferably from about 5 to about 10 percent. Thegranulation is then preferably dried. Thereafter, the granulate may befurther formulated into an appropriate oral dosage form, for example, bycompression of the resulting granulate into appropriately sized tablets,by filling gelatin capsules with an appropriate amount of the granulate(with or without compression of the granulate), as well as use in themanufacture of other oral dosage forms known to those skilled in theart. This embodiment may be particularly beneficial to reduce the amountof drug released during the initial phases of dissolution when theformulation is exposed to fluid in an environment of use, e.g., in vitrodissolution or in the gastrointestinal tract.

An effective amount of any generally accepted pharmaceutical lubricant,including the calcium or magnesium soaps may be added to theabove-mentioned ingredients of the excipient be added at the time themedicament is added, or in any event prior to compression into a saiddosage form. An example of a suitable lubricant is magnesium stearate inan amount of about 0.5 to about 3% by weight of the solid dosage form.An especially preferred lubricant is sodium stearyl fumarate, NF,commercially available under the trade name Pruv® from the EdwardMendell Co., Inc.

The sustained release excipients of the present invention have uniformpacking characteristics over a range of different particle sizedistributions and are capable of processing into the final dosage form(e.g., tablets) using either direct compression, following addition ofdrug and lubricant powder, or conventional wet granulation.

The properties and characteristics of a specific excipient systemprepared according to the present invention is dependent in part on theindividual characteristics of the homo and hetero polysaccharideconstituents, in terms of polymer solubility, glass transitiontemperatures etc., as well as on the synergism both between differenthomo- and heteropolysaccharides and between the homo andheteropolysaccharides and the inert saccharide constituent(s) inmodifying dissolution fluid-excipient interactions.

The combination of the gelling agent (i.e., a mixture of xanthan gum andlocust beam gum) with the inert diluent provides a ready-to-use productin which a formulator need only blend the desired active medicament andan optional lubricant with the excipient and then compress the mixtureto form slow release tablets. The excipient may comprise a physicaladmix of the gums along with a soluble excipient such as compressiblesucrose, lactose or dextrose, although it is preferred to granulate oragglomerate the gums with plain (i.e., crystalline) sucrose, lactose,dextrose, etc., to form an excipient. The granulate form has certainadvantages including the fact that it can be optimized for flow andcompressibility; it can be tableted, formulated in a capsule, extrudedand spheronized with an active medicament to form pellets, etc.

The pharmaceutical excipients prepared in accordance with the presentinvention may be prepared according to any agglomeration technique toyield an acceptable excipient product. In dry granulation techniques,the excipients, i.e., the desired amounts of the heteropolysaccharidegum, the homopolysaccharide gum, and the inert diluent are mixed with anactive medicament and the mixture is then formed into tablets and thelike by compression, without the addition of water or other solvent.

In wet granulation techniques, the desired amounts of theheteropolysaccharide gum, the homopolysaccharide gum, and the inertdiluent are mixed together and thereafter a moistening agent such aswater, propylene glycol, glycerol, alcohol or the like is added toprepare a moistened mass. Next, the moistened mass is dried. The driedmass is then milled with conventional equipment into granules.Therefore, the excipient product is ready to use.

The sustained release excipient is free-flowing and directlycompressible. Accordingly, the excipient may be mixed in the desiredproportion with a therapeutically active medicament and optionallubricant (dry granulation). Alternatively, all or part of the excipientmay be subjected to a wet granulation with the active ingredient andthereafter tableted. When the final product to be manufactured istablets, the complete mixture, in an amount sufficient to make a uniformbatch of tablets, is then subjected to tableting in a conventionalproduction scale tableting machine at normal compression pressure, i.e.about 2000-1600 lbs/sq in. However, the mixture should not be compressedto such a degree that there is subsequent difficulty in its hydrationwhen exposed to gastric fluid.

One of the limitations of direct compression as a method of tabletmanufacture is the size of the tablet. If the amount of active (drug) ishigh, a pharmaceutical formulator may choose to wet granulate the activemedicament with other excipients to attain a more compact tablet.Usually the amount of filler/binder or excipients needed in wetgranulation is less than that in direct compression since the process ofwet granulation contributes to some extent toward the desired physicalproperties of a tablet.

The average tablet size for round tablets is preferably about 300 mg to750 mg and for capsule-shaped tablets about 750 mg to 1000 mg.

The average particle size of the granulated excipient of the presentinvention ranges from about 50 microns to about 400 microns andpreferably from about 185 microns to about 265 microns. The particlesize of the granulation is not narrowly critical, the importantparameter being that the average particle size of the granules, mustpermit the formation of a directly compressible excipient which formspharmaceutically acceptable tablets. The desired tap and bulk densitiesof the granulation of the present invention are normally between fromabout 0.3 to about 0.8 g/ml, with an average density of from about 0.5to about 0.7 g/ml. For best results, the tablets formed from thegranulations of the present invention are from about 6 to about 8 kghardness. The average flow of the granulations prepared in accordancewith the present invention are from about 25 to about 40 g/sec. Tabletscompacted using an instrumented rotary tablet machine have been found topossess strength profiles which are largely independent of the inertsaccharide component. Scanning electron photomicrographs of largelytablet surfaces have provided qualitative evidence of extensive plasticdeformation on compaction, both at the tablet surface and across thefracture surface, and also show evidence of surface pores through whichinitial solvent ingress and solution egress may occur.

In certain embodiments of the invention, the tablet is coated with asufficient amount of a hydrophobic material, such as, e.g., ahydrophobic polymer, to render the formulation capable of providing arelease of the medicament such that a 12 or 24 hour formulation isobtained. The hydrophobic material included in the tablet coating may bethe same or different material as compared to the hydrophobic materialwhich is optionally granulated with the sustained release excipient.

In other embodiments of the present invention, the tablet coating maycomprise an enteric coating material in addition to or instead or thehydrophobic coating. Examples of suitable enteric polymers includecellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,polyvinylacetate phthalate, methacrylic acid copolymer, shellac,hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate,and mixtures of any of the foregoing. An example of a suitablecommercially available enteric material is available under the tradename Eudragit™ L 100-555.

In further embodiments, the dosage form may be a coating with ahydrophilic coating in addition to or instead of the above-mentionedcoatings. An example of a suitable material which may be used for such ahydrophilic coating is hydroxypropylmethylcellulose (e.g., Opadry®,commercially available from Colorcon, West Point, Pa.).

The coatings may be applied in any pharmaceutically acceptable mannerknown to those skilled in the art. For example, in one embodiment, thecoating is applied via a fluidized bed or in a coating pan. For example,the coated tablets may be dried, e.g., at about 60-70° C. for about 3-4hours in a coating pan. The solvent for the hydrophobic material orenteric coating may be organic, aqueous, or a mixture of an organic andan aqueous solvent. The organic solvents may be, e.g., isopropylalcohol, ethanol, and the like, with or without water.

In additional embodiments of the present invention, a support platformis applied to the tablets manufactured in accordance with the presentinvention. Suitable support platforms are well known to those skilled inthe art. An example of suitable support platforms is set forth, e.g., inU.S. Pat. No. 4,839,177, hereby incorporated by reference herein in itsentirety. In that patent, the support platform partially coats thetablet, and consists of a polymeric material insoluble in aqueousliquids. The support platform may, for example, be designed to maintainits impermeability characteristics during the transfer of thetherapeutically active medicament. The support platform may be appliedto the tablets, e.g., via compression coating onto part of the tabletsurface, by spray coating the polymeric materials comprising the supportplatform onto all or part of the tablet surface, or by immersing thetablets in a solution of the hydrophobic materials.

The support platform may have a thickness of, e.g., about 2 mm ifapplied by compression, and about 10 μ if applied via spray-coating orimmersion-coating. Generally, in embodiments of the invention wherein ahydrophobic material or enteric coating is applied to the tablets, thetablets are coated to a weight gain from about 1 to about 20%, and incertain embodiments preferably from about 5% to about 10%.

Materials useful in the hydrophobic coatings and support platforms ofthe present invention include derivatives of acrylic acid (such asesters of acrylic acid, methacrylic acid, and copolymers thereof)celluloses and derivatives thereof (such as ethylcellulose),polyvinylalcohols, and the like.

In certain embodiments of the present invention, the tablet coreincludes an additional dose of the medicament included in either thehydrophobic or enteric coating, or in an additional overcoating coatedon the outer surface of the tablet core (without the hydrophobic orenteric coating) or as a second coating layer coated on the surface ofthe base coating comprising the hydrophobic or enteric coating material.This may be desired when, for example, a loading dose of atherapeutically active agent is needed to provide therapeuticallyeffective blood levels of the active agent when the formulation is firstexposed to gastric fluid. The loading dose of medicament included in thecoating layer may be, e.g., from about 10% to about 40% of the totalamount of medicament included in the formulation.

Albuterol Controlled Release Formulation

In a more preferred embodiment, the therapeutically active agent isalbuterol, or salts or derivatives thereof (e.g., albuterol sulfate).Albuterol sulfate is a beta2-selective adrenergic agonist and isindicated for the relief of bronchospasm in patients with reversibleobstructive airway disease. Patient compliance and evenly maintainedblood levels of the active drug are important for achieving good controlof the symptoms of bronchospasm in such patients. The half-life ofalbuterol sulfate in the human body is only about 5 hours. Thus, acontrolled release form for the sustained delivery of albuterol providesimproved patient compliance by reducing the number of doses per day andalso provides more consistent blood levels of albuterol for patients inneed of such treatment.

The albuterol controlled release formulation is composed of synergisticheterodisperse polysaccharides together with a saccharide component. Thesynergism between the homo- and hetero-polysaccharide components enablesthe manipulation of different rate controlling mechanisms. In order toachieve appropriate drug release, the saccharides were optimized basedupon the magnitude of interactions and the ratio of one saccharide toanother.

Preparation

The albuterol containing formulation according to the invention isprepared, for example, by dry blending the components, e.g., aheteropolysaccharide, a homopolysaccharide, an inert filler, and ahydrophobic material, followed by the addition of a suitable amount ofwater, with continued blending, followed by dry granulation in a fluidbed dryer and then milling of the resulting granulation product.Albuterol sulfate, in an amount ranging from, e.g., about 2 throughabout 50% by weight of the total formulation, or preferably from about 1through about 10% by weight or more preferably from about 1 throughabout 6% by weight of the total formulation, is then compounded with thegranulation product and formed into pills, caplets or capsules. Whateverthe formulation, it is preferred that such pills, caplets or capsuleseach contain an effective therapeutic amount of albuterol or aderivative or salt thereof. Simply by way of example, the pills, capletsor capsules can contain an amount of albuterol sulfate equivalent toabout 4 to about 16 mg of albuterol free base per dosage unit of thefree base. More preferably, the pills, caplets or capsules can containan amount of albuterol sulfate equivalent to about 8 to about 12 mg ofthe free base. Simply by way of comparison, 9.6 mg of albuterol sulfateis equivalent to 8 mg of free base. Effective amounts of otherpharmaceutically acceptable albuterol derivatives or salts thereof maybe used, with the amounts adjusted in proportion to the weight rangesprovided for albuterol free base.

Dissolution Testing

The test formulations were evaluated under a variety of dissolutionconditions to determine the effects of pH, media, agitation andapparatus. Dissolution tests were performed using a USP Type III (VanKelBio-Dis II) apparatus. Effects of pH, agitation, polarity, enzymes andbile salts were evaluated.

Bioavailability Study

A study was conducted to evaluate the bioavailability of a testformulation of albuterol sulfate using a randomized, balanced, openlabel, single dose, crossover design. The study was performed using 12healthy male and female volunteers between the ages of 18 and 35. Bloodsamples were removed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 15 and 25hours. Except for the "fed" treatment in which the subjects received astandard high fat breakfast, no food was allowed until a standard lunchwas served four hours after the dose was administered. The data fromeach time point were used to derive pharmacokinetic parameters: areaunder plasma concentration-time curve ("AUC") such as AUC0-t, AUC0-∞,mean peak plasma concentration ("Cmax") and time.sub.Δ to mean peakplasma concentration ("Tmax") which data confirmed that the formulationaccording to the invention provided controlled release of albuterolsulfate.

The invention is further described in the following examples, based uponthe above described methods, which are in no way intended to limit thescope of the invention.

EXAMPLES 1-2 Preparation of Controlled Release Formulations withCarboxymethylcellulose and Dissolution Tests Thereon

The sustained release excipient was prepared by dry blending therequisite amounts of xanthan gum, locust bean gum, a pharmaceuticallyacceptable hydrophobic polymer and an inert diluent in a high-speedmixer/granulator for 2 minutes. While running choppers/impellers, thewater was added and the mixture was granulated for another 2 minutes.The granulation was then dried in a fluid bed dryer to a loss on dryingweight ("LOD") of between 4 and 7%. The granulation was then milledusing 20 mesh screens. The ingredients of the sustained releaseexcipients used for Examples 1-2 are set forth in Table 1 below:

                  TABLE 1    ______________________________________    The hydrophobic polymer is    carboxymethylcellulose ("CMC").    Component         Example 1                               Example 2    ______________________________________    1.     Xanthan gum      10%      10%    2.     Locust bean gum                          10       10    3.     CMC            10       30    4.     Dextrose       70       50    5.     Water           23*      23*    ______________________________________     *Removed during processing.

Next, the sustained release excipient prepared as detailed above is dryblended with a desired amount of medicament (in the following examplesthe medicament is albuterol sulfate), in a V-blender for 10 minutes. Asuitable amount of tableting lubricant Pruv® (sodium stearyl fumarate,NF, commercially available from the Edward Mendell Co., Inc.) for thefollowing examples is added and the mixture is blended for another 5minutes. This final mixture is compressed into tablets, each tabletcontaining 2.9% (Ex. 1) or 4.7% (Ex. 2) by weight, respectively, ofalbuterol sulfate. The tablets produced by Examples 1 and 2 weighed334.6 mg and 204.7 mg, respectively. The proportions of the tablets ofExamples 1 and 2 are set forth in Table 2 below.

                  TABLE 2    ______________________________________    Component          Example 1                                Example 2    ______________________________________    1.    SRE*             95.6%    93.8%    2.    Albuterol sulfate                           2.9      4.7    3.    Sodium stearyl fumarate                           1.5      1.5    ______________________________________     *Sustained release excipient.

Dissolution tests were then carried out on the tablets of Examples 1 and2. The dissolution tests were conducted in an automated USP dissolutionapparatus (Paddle Type II, pH 7.5 buffer, 50 rpm in 500 mL.) The resultsare set forth as percent release as a function of time, in hours.

                  TABLE 3    ______________________________________                  Example 1                         Example 2    ______________________________________    Time (hrs)     0 (% release)  0.0      0.0     2              28.2     30.7     4              41.5     49.5     6              54.5     67.2     8              64.3     79.8    10              71.0     91.2    12              78.7     96.5    Tablet wt (mg)  334.6    204.7    Diameter (in)   3/8      3/8    Hardness (Kp)   6.5      2.6    ______________________________________

The tablet of Example 1, with a higher percentage of sustained releaseexcipient, provided the most prolonged release in the dissolution test.

EXAMPLES 3-4 Preparation of Controlled Release Formulations withCellulose Acetate Phthalate and Dissolution Tests Thereon

The sustained release excipient was prepared by dry blending therequisite amounts of xanthan gum, locust bean gum, a pharmaceuticallyacceptable hydrophobic polymer and an inert diluent as described forExamples 1-2, supra, but with cellulose acetate phthalate ("CAP") as thehydrophobic polymer, as detailed by Table 4, below, for Examples 3 and4.

                  TABLE 4    ______________________________________    Component         Example 3                               Example 4    ______________________________________    1.     Xanthan gum      15%      15%    2.     Locust bean gum                          15       15    3.     CAP            10       30    4.     Dextrose       60       40    5.     Water           10*      17*    ______________________________________     *Removed during processing.

Next, the sustained release excipient prepared as detailed above was dryblended with a desired amount of albuterol sulfate, as described forExamples 1-2, supra. This final mixture was then compressed intotablets, each tablet containing 2.9% by weight of albuterol sulfate. Thetablets produced by Examples 3 and 4 weighed 334.6 mg. The proportionsof the tablets of Examples 3 and 4 are set forth in Table 5 below:

                  TABLE 5    ______________________________________    Component          Example 3                                Examples 4    ______________________________________    1.    SRE*              95.6%    95.6%    2.    Albuterol sulfate                           2.9      2.9    3.    Sodium stearyl fumarate                           1.5      1.5    ______________________________________     *Sustained release excipient.

Dissolution tests were then carried out on the tablets of Examples 3 and4. The dissolution tests were conducted in an automated USP dissolutionapparatus in such a way as to model passage through the gastrointestinaltract, in the stomach (acid buffer with a pH of 1.5 for time: 0 though 1hour) and in the intestines (alkaline buffer with a pH of 7.5 for time:1 through 12 hours) (Paddle Type II, 50 rpm in 500 mL.) The results areset forth as percent release as a function of time, in hours, in Table 6below.

                  TABLE 6    ______________________________________                  Example 3                         Example 4    ______________________________________    Time (hrs)     0 (% release)  0.0      0.0     1              36.0     36.2     2              50.2     49.4     4              65.1     61.4     6              73.5     70.7     8              83.1     77.0    10              86.3     81.6    12              91.0     86.1    Tablet wt (mg)  334.6    334.6    Diameter (in)   3/8      3/8    Hardness (Kp)   5.8      5.8    ______________________________________

The tablet tested in Example 4 provided the most prolonged release inthe dissolution test.

EXAMPLES 5-6 Preparation of Controlled Release Formulations withPolyvinyl Acetate Phthalate and Dissolution Tests Thereon

The sustained release excipient was prepared by dry blending therequisite amounts of xanthan gum, locust bean gum, a pharmaceuticallyacceptable hydrophobic polymer and an inert diluent as described forExamples 1-2, supra, but with polyvinyl acetate phthalate ("PVAP") asthe hydrophobic polymer, as detailed by Table 7, below, for Examples 5and 6.

                  TABLE 7    ______________________________________    Component         Example 5                               Example 6    ______________________________________    1.     Xanthan gum      15%      15%    2.     Locust bean gum                          15       15    3.     PVAP           10       30    4.     Dextrose       60       40    5.     Water           18*      23*    ______________________________________     *Removed during processing.

Next, the sustained release excipient prepared as detailed above was dryblended with a desired amount of albuterol sulfate, as described forExamples 1-2, supra. This final mixture was then compressed intotablets, each tablet containing 2.9% by weight of albuterol sulfate. Thetablets produced by Examples 5 and 6 weighed 334.6 mg, respectively. Theproportions of the tablets of Examples 5 and 6 are set forth in Table 8below:

                  TABLE 8    ______________________________________    Component          Example 5                                Example 6    ______________________________________    1.    SRE*              95.6%    95.6%    2.    Albuterol sulfate                           2.9      2.9    3.    Sodium stearyl fumarate                           1.5      1.5    ______________________________________     *Sustained release excipient.

Dissolution tests were then carried out on the tablets of Examples 5 and6. The dissolution tests were conducted in an automated USP dissolutionapparatus in such a way as to model passage through the gastrointestinaltract, in the stomach (acid buffer with a pH of 1.5 for time: 0 though 1hour) and in the intestines (alkaline buffer with a pH of 7.5 for time:1 through 12 hours) (Paddle Type II, 50 rpm in 500 mL.) The results areset forth as percent release as a function of time, in hours, in Table 9below.

                  TABLE 9    ______________________________________                  Example 5                         Example 6    ______________________________________    Time (hrs)     0 (% release)  0.0      0.0     1              36.4     36.5     2              51.3     47.4     4              66.2     57.6     6              71.8     66.0     8              79.9     70.4    10              84.2     77.2    12              86.4     77.7    Tablet wt (mg)  334.6    334.6    Diameter (in)   3/8      3/8    Hardness (Kp)   5.9      8.6    ______________________________________

The tablet tested in Example 6 provided the most prolonged release inthe dissolution test.

EXAMPLES 7-8 Preparation of Controlled Release Formulations withHydroxypropylmethylcellulose Phthalate and Dissolution Tests Thereon

The sustained release excipient was prepared by dry blending therequisite amounts of xanthan gum, locust bean gum, a pharmaceuticallyacceptable hydrophobic polymer and an inert diluent as described forExamples 1-2, supra, but with hydroxypropylmethylcellulose phthalate("HPMCP") as the hydrophobic polymer, as detailed by Table 10, below,for Examples 7 and 8.

                  TABLE 10    ______________________________________    Component         Example 7                               Example 8    ______________________________________    1.     Xanthan gum      15%      15%    2.     Locust bean gum                          15       15    3.     HPMCP          10       30    4.     Dextrose       60       40    5.     Water           13*      18*    ______________________________________     *Removed during processing.

As for the previous examples, the sustained release excipient wasprepared as detailed above and then dry blended with a desired amount ofalbuterol sulfate, as described for Examples 1-2, supra. This finalmixture was then compressed into tablets, each tablet containing 2.9% byweight of albuterol sulfate. The tablets produced by Examples 7 and 8weighed 334.6 mg, respectively. The proportions of the tablets ofExamples 7 and 8 are set forth in Table 11 below:

                  TABLE 11    ______________________________________    Component          Example 7                                Example 8    ______________________________________    1.    SRE*             95.6%    95.6%    2.    Albuterol sulfate                           2.9      2.9    3.    Sodium stearyl fumarate                           1.5      1.5    ______________________________________     *Sustained release excipient.

The dissolution tests were conducted in an automated USP dissolutionapparatus in such a way as to model passage through the gastrointestinaltract, as described supra for, e.g., Examples 5-6. The results are setforth as percent release as a function of time, in hours, in Table 12below.

                  TABLE 12    ______________________________________                  Example 7                         Example 8    ______________________________________    Time (hrs)     0 (% release)  0.0      0.0     1              33.7     32.7     2              48.2     42.8     4              63.9     60.3     6              74.8     71.2     8              79.6     74.6    10              85.6     82.3    12              87.0     87.2    Tablet wt (mg)  334.6    334.6    Diameter (in)   3/8      3/8    Hardness (Kp)   6.5      8.3    ______________________________________

The data of Table 12 indicates that both Examples 7 and 8 providedeffective prolongation of albuterol release in the dissolution test.

EXAMPLES 9-12 Preparation of Controlled Release Formulations withEthylcellulose Coating and Dissolution Tests Thereon

The sustained release excipient was prepared by dry blending therequisite amounts of xanthan gum, locust bean gum and an inert diluentas described for Examples 1-2, supra, but with no hydrophobic polymer,and with an extra 2 minutes of granulation after the addition of thecomponents (for 4 total minutes of post-addition granulation).Ethylcellulose aqueous dispersion was substituted for water in the abovemethods. The components of the excipient for Examples 9-12 are detailedby Table 13, below.

                  TABLE 13    ______________________________________    Component      Excipient for Examples 9-12    ______________________________________    1.     Xanthan gum   12%    2.     Locust bean gum                       18    3.     Dextrose    65    4.     EAD*         5*    ______________________________________     *EAD is an ethylcellulose aqueous dispersion containing approximately 25%     by weight of solids. The amount added to the formulation (i.e., 5%) is     solids only. Available commercially as, e.g., Surelease ®, from     Colorcon.

The xanthan gum and locust bean gum was dry blended in a V-blender for10 minutes, the dextrose was added and the mixture blended for another 5minutes. The EAD was then added, followed by an additional 5 minutes ofblending. The resulting granulation was then compressed into tabletswith sodium stearyl fumarate, as a tableting lubricant. The tablets werethen coated with additional ethylcellulose aqueous dispersion. Toaccomplish this, ethylcellulose (Surelease®, 400 g) was mixed with water(100 g) to form an aqueous suspension. Thereafter, the tablets werecoated in a Keith Machinery coating pan (diameter 350 mm; pan speed 20rpm; spray-gun nozzle 0.8 mm; tablets bed temperature 40°-50° C.; chargeper batch 1 kg; dry air--Conair Prostyle 1250, 60°-70° C.). The tabletswere coated to a weight gain of about 5%.

The tablets weighed 181.4 mg, respectively. The proportions of thetablets are set forth in Table 14 below:

                  TABLE 14    ______________________________________    Component           Percent    ______________________________________    1.      SRE*            8.2%    2.      Albuterol sulfate                            5.3    3.      Polyvinyl acetate phthalate                            5.0    4.      Sodium stearyl fumarate                            1.5    ______________________________________     *Sustained release excipient.

The dissolution tests were conducted in an automated USP dissolutionapparatus in such a way as to model passage through the gastrointestinaltract, as described supra for, e.g., Examples 5-6. The results are setforth as percent release as a function of time, in hours, in Table 15,below. The columns are identified as "Uncoated" (Ex. 9) 2% (Ex. 10), 3%(Ex. 11) and 4% (Ex. 12) coating by weight.

                  TABLE 15    ______________________________________             Ex. 9    Ex. 10   Ex. 11 Ex. 12    Time (hrs)             Uncoated 2%       3%     4% (coat % w/w)    ______________________________________     0 (% release)             0.0      0.0      0.0    0.0     1       41.7     11.2     0.0    0.0     2       56.7     21.9     2.3    0.0     4       73.0     41.2     16.2   4.6     6       82.5     60.3     37.1   21.3     8       87.9     74.9     54.5   40.3    10       91.0     82.5     65.2   54.0    12       93.9     88.5     84.1   67.5    ______________________________________     Tablet wt (mg) 181.4     Diameter (in) 3/8     Hardness (Kp) 7.9

The above table clearly indicates that a prolongation of release isobtained that is proportional to the percent of hydrophobic coating, byweight.

In order to determine the differences, if any, in dissolution kineticsbetween a fed state and a fasting state for the series of coated tabletsas tested above in Examples 9-12, the same tablets were tested, invitro, for dissolution rates in a solution containing 30% peanut oil("fed") to model a gastrointestinal tract with a typical dietary fatload. The control determined the dissolution rates in a solution lackingthe fat load ("fasted"). The pH--time protocol (ranging from acid toalkaline to model digestive processes) is set forth below in Table 16,below.

                  TABLE 16    ______________________________________    Fed/Fast Dissolution Protocol              "Fasted"  "Fed"    ______________________________________    Apparatus:  Type III    Type III    Media:      0-1 hr pH 1.5                            30% peanut oil                1-2 hr pH 3.5                2-4 hr pH 5.5                 4-12 hr pH 7.5    Agitation:  15 cpm      15 cpm    Volume:     250 mL      250 mL    ______________________________________

                  TABLE 17    ______________________________________    Fed/Fast Dissolution Results               "Fasted" "Fasted"   "Fed"  "Fed"    Time (hrs) Uncoated 2%         Uncoated                                          2%    ______________________________________     0 (% release)               0.0      0.0        0.0    0.0     1         48.8     15.5       28.8   18.4     2         68.5     28.8       49.8   39.9     4         87.2     49.5       91.9   78.9     6         96.1     65.9       100.0  97.3     8         100.0    80.7       100.0  100.0    12         100.0    100.0      100.0  100.0    ______________________________________

As can be appreciated from table 17, the dissolution rates (in vitro) inthe presence of 30% peanut oil ("Fed") are not significantly differentfrom the dissolution rates in the absence of the 30% peanut oil("Fast"), thus demonstrating both the improved control of release rateprovided by the 2% ethylcellulose coating and the freedom fromsignificant "Fed/Fast" effects provided by the formulations of thepresent invention.

Results and Discussion

FIGS. 1 and 2 show in vitro dissolution profiles for the productformulated according to Table 14 and Table 15 (Example 10) i.e., theformulation of Table 14 with a 2% ethylcellulose coating. The mean invivo plasma profile for the test product is provided in FIG. 3. FIG. 1shows a dissolution profile of an albuterol containing tablet formulatedaccording to Table 14 and Table 15 (Example 10) as described above. Thedissolution profile of FIG. 1 was conducted as a Type II dissolutionwith a pH change to simulate gastric and enteric passage and stirring at50 rpm (acid buffer with a pH of 1.5 for time: 0 though 1 hour followedby alkaline buffer with a pH of 7.5 for time: 1 through 12 hours). FIG.2 shows a dissolution profile of an albuterol containing tabletformulated formulated according to Table 14 and Table 15 as describedabove and conducted as a Type III dissolution with a pH change tosimulate gastric and enteric passage (pH profile as described by Table16 above) and stirring at 15 rpm. FIG. 3 shows an albuterol plasmaprofile of provided by ingestion of an albuterol containing tabletformulated formulated according to Table 14 and Table 15 (Example 10):solid circles mark curve of plasma profile in fed subject; open circlesmark curve of plasma profile in fasted subjects.

Analysis of the pharmacokinetic parameters C_(max), T_(max), and AUC₂₈(Table 18) confirms that the tested formulation is an ideal candidatefor a 12 hour albuterol formulation. Furthermore, a comparison of thetest product in the fed and fasted states show that the test product isnot significantly affected by food. A delay of gastric emptying, whichis expected in the fed state, accounts for the extended time required toreach the maximum plasma concentration.

                  TABLE 18    ______________________________________    Albuterol Pharmacokinetics    ______________________________________                   TIMERx   TIMERx    Parameter      fasted   fed    ______________________________________    Cmax    mean           10.5     10.6    % CV           39.0     31.0    Tmax    mean           4.5      7.0    % CV           29.0     23.0    AUCInf    mean           113.4    128.1    % CV           30.0     20.0    ______________________________________                                       AUC    Ratios           Cmax       Tmax   Inf    ______________________________________    TIMERx fasted:TIMERx fed                     0.98       0.64   0.89    TIMERx fed:TIMERx fasted                     1.02       1.57   1.13    ______________________________________                  Cmax   Cmax     AUCInf                                        AUCInf    Confidence Limits                  LL     UL       LL    UL    ______________________________________    TIMERx fed vs 89     124      102   133    TIMERx fasted    ______________________________________

                  TABLE 19    ______________________________________    Parameter     TIMERx-fasted                             TIMERx-fed    ______________________________________    AUC.sub.oo     57.3-156.2                              75.6-161.1    Cmax           4.6-18.4   6.0-15.9    Tmax          3.0-6.0    3.0-8.0    ______________________________________           Parameter                  TIMERx-fed    ______________________________________           AUC.sub.oo                   89.9-149.2           Cmax    7.0-11.9           Tmax    3.0-10.0    ______________________________________

Conclusion

From the results provided in above examples, it can be seen that theformulations according to the invention provide a controlled release ofan active medicament such as albuterol sulfate without any significantdifferences induced by a "fed/fast" effect due to the presence of foodin the gastrointestinal tract. Accordingly, the results provide that thetablets produced according to the invention are suitable for deliveringmedicaments as an oral solid dosage form over a 24-hour oral period oftime.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the claims.Various publications are cited herein, the disclosures of which areincorporated by reference in their entireties.

What is claimed is:
 1. A controlled release solid dosage form for oraladministration of a therapeutically active medicament to a patient inneed thereof, comprising:a pharmaceutically effective amount of amedicament to be administered to a patient in need of said medicament; asustained release excipient comprising a gelling agent; apharmaceutically acceptable hydrophobic material; and an inertpharmaceutical diluent wherein the ratio of said inert diluent to saidgelling agent is from about 1:8 to about 8:1, said dosage form providinga sustained release of said medicament when exposed to an environmentalfluid.
 2. The controlled release solid dosage form according to claim 1wherein said inert diluent is selected from the group consisting ofpharmaceutically acceptable saccharides, polyhydric alcohols,pre-manufactured direct compression diluents, and mixtures of any of theforegoing.
 3. The controlled release solid dosage form according toclaim 1, wherein said hydrophobic material is selected from the groupconsisting of a cellulose ether, a cellulose ester and analkylcellulose.
 4. The controlled release solid dosage form according toclaim 1, wherein said hydrophobic material is selected from the groupconsisting of ethylcellulose, carboxymethylcellulose, cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate and a polyvinylacetate polymer.
 5. The controlled release solid dosage form accordingclaim 1, wherein said hydrophobic material is present in an amountranging from about 25 percent to about 50 percent, by weight, of thesolid dosage form.
 6. The controlled release solid dosage form accordingto claim 1, wherein said medicament is a pharmaceutically effectiveamount of albuterol or a salt or derivative thereof.
 7. The controlledrelease solid dosage form according to claim 1 which is a tablet.
 8. Thecontrolled release solid dosage form according to claim 1, which is ingranulate form.
 9. The controlled release solid dosage form according toclaim 8, wherein said granulate is coated with a hydrophobic material toa weight gain from about 1 percent to about 20 percent.
 10. Thecontrolled release solid dosage form according to claim 1, wherein themedicament comprises an amount of albuterol equivalent to about 4 mg toabout 16 mg of albuterol free base.
 11. A method of preparing acontrolled release solid dosage form comprising a medicament for oraladministration, the method comprisingpreparing of a sustained releaseexcipient comprising from about 10 to about 99 percent by weight of agelling agent, from about 0 to about 89 percent by weight of an inertpharmaceutical diluent, and from about 1 to about 90 percent by weightof a pharmaceutically acceptable hydrophobic material; and adding atherapeutically effective amount of a medicament to said excipient, suchthat a final product is obtained having a ratio of said medicament tosaid gelling agent from about 1:3 to about 1:8, wherein said formulationprovides therapeutically effective blood levels of said medicament forat least 12 hours.
 12. The method of claim 11, further comprisingcompressing said mixture of said sustained release excipient and saidmedicament into tablets.
 13. The method of claim 11, wherein saidmedicament is albuterol or a salt or derivative thereof.
 14. The methodof claim 13, further comprising coating the resultant tablets with ahydrophobic coating to a weight gain from about 1 percent to about 20percent.
 15. A method of treating a patient with albuterolcomprising:preparing a sustained release excipient comprising from about10 to about 99 percent by weight of a gelling agent from about 0 toabout 89 percent by weight of an inert pharmaceutical diluent, and fromabout 1 to 90 percent by weight of a pharmaceutically acceptablehydrophobic material; and adding an effective amount of albuterol or asalt or derivative thereof to said sustained release excipient,tableting the resultant mixture into tablets such that said tablets havea ratio of albuterol to said gelling agent from about 1:3 to about 1:8,such that a gel matrix is created when said tablet is exposed togastrointestinal fluid and said tablet provides therapeuticallyeffective blood levels of albuterol for at least 12 hours; andadministering said tablet to a patient on a once-a-day or twice-a-daybasis.
 16. The method of claim 15, further comprising preparing saidformulation such that it provides therapeutically effective blood levelsof said medicament for at least 24 hours.